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Involvement of phospholipase A₂ in Pseudomonas aeruginosa-mediated PMN transepithelial migration

¹Mucosal Immunology Laboratories, Massachusetts General Hospital, Charlestown, Massachusetts; and ²Department of Microbiology and Molecular Genetics, Harvard Medical School, Boston, Massachusetts

Submitted 12 September 2005 ; accepted in final form 27 October 2005

Inflammation resulting from bacterial infection of the respiratory mucosal surface during pneumonia and cystic fibrosis contributes to pathology. A major consequence of the inflammatory response is recruitment of polymorphonuclear cells (PMNs) to the infected site. To reach the airway, PMNs must travel through several cellular and extracellular barriers, via the actions of multiple cytokines, chemokines, and adhesion molecules. Using a model of polarized lung epithelial cells (A549 or Calu-3) grown on Transwell filters and human PMNs, we have shown that Pseudomonas aeruginosa induces PMN migration across lung epithelial barriers. The process is mediated by epithelial production of the eicosanoid hepoxilin A₃ (HXA₃) in response to P. aeruginosa infection. HXA₃ is a PMN chemoattractant metabolized from arachidonic acid (AA). Given that release of AA is believed to be the rate-limiting step in generating eicosanoids, we investigated whether P. aeruginosa infection of lung epithelial cells resulted in an increase in free AA. P. aeruginosa infection of A549 or Calu-3 monolayers resulted in a significant increase in [³H]AA released from prelabeled lung epithelial cells. This was partially inhibited by PLA₂ inhibitors ONO-RS-082 and ACA as well as an inhibitor of diacylglycerol lipase. Both PLA₂ inhibitors dramatically reduced P. aeruginosa-induced PMN transmigration, whereas the diacylglycerol lipase inhibitor had no effect. In addition, we observed that P. aeruginosa infection caused an increase in the phosphorylation of cytosolic PLA₂ (cPLA₂), suggesting a mechanism whereby P. aeruginosa activates cPLA₂ generating free AA that may be converted to HXA₃, which is required for mediating PMN transmigration.

lung inflammation; arachidonic acid; eicosanoid; polymorphonuclear cells; neutrophils

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